The Need to Decide If All Estrogens Are Intrinsically Similar

Article excerpt

We used gene expression profiling m investigate whether the molecular effects induced by estrogens of different provenance are intrinsically similar. In this article we show that the physiologic estrogen 17[beta]-estradiol, the phytoestrogen genistein, and the synthetic estrogen diethylstilbestrol alter the expression of the same 179 genes in the intact immature mouse uterus under conditions where each chemical has produced an equivalent gravimetric and histologic uterotrophic effect, using the standard 3-day assay protocol. Data are also presented indicating the limitations associated with comparison of gene expression profiles for different chemicals at times before the uterotrophic effects are fully realized. We conclude that the case has yet to be made for regarding synthetic estrogens as presenting a unique human hazard compared with phytoestrogens and physiologic estrogens. Key words: diethylstilbestrol, estrogen, gene expression, genistein, microarray, phytoestrogen, toxicogenomics, uterus. Environ Health Perspect 112:1137-1142 (2004). doi:10.1289/ehp.7028 available via http://dx.doi.org/[Online 19 May 2004]

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The question of whether phytoestrogens and synthetic estrogens are toxicologically similar, or intrinsically different, presents a challenge to all involved in human hazard and risk assessments. Although there is a general concern that exposure to nanogram or microgram amounts of environmental estrogens may be associated with adverse health effects, in the public mind there is a widespread belief that foods and dietary supplements containing milligram quantities of phytoestrogens confer only health benefits. An implicit distinction therefore seems to have been drawn between synthetic and plant-derived estrogens--a belief sustained in the public mind by the assumption that natural is good and synthetic is bad--but an untested and potentially misleading notion for those involved with science-based human hazard/risk assessments.

Phytoestrogens and synthetic estrogens are generally considered separately in the literature. For example, Howdeshell et al. (1999) suggested a possible association between the advance in first estrus observed in mice exposed in utero to 2.4 [micro]g/kg of the synthetic environmental estrogen bisphenol A and reports of an increased incidence of hypospadias in boys (Paulozzi et al. 1997) and the earlier sexual maturation of girls (Herman-Giddens et al. 1997)--the implication being that synthetic estrogens present a greater hazard than the much higher levels of phytoestrogens being consumed by those same children. In contrast, there are reports of an increased incidence of hypospadias in boys born to vegetarians (North and Golding 2000), of alterations in the menstrual cycle (Cassidy et al. 1994), and of reduced breast cancer incidences (Messina 1999) among women eating diets rich in phytoestrogens. Support for these epidemiologic observations comes from experimental studies indicating that advances in sexual development in rodents can be induced by their exposure to phytoestrogens (Casanova et al. 1999; Cassidy and Fanghnan 2000; Safe et al. 2002). In contrast to these separate lines of inquiry, Newbold and colleagues have evaluated potential similarities between natural and synthetic estrogens. In seminal studies, they demonstrated that neonatal exposure of female mice to equipotent uterotrophic doses of the phytoestrogen genistein (GEN; Figure 1) or the synthetic estrogen diethylstilbestrol (DES) leads to an identical incidence of uterine adenomas at 18 months of age (Newbold et al. 2001). However, in attempting to draw parallels, or distinctions, between phytoestrogens and synthetic estrogens, it is imperative to consider growing awareness of the complexity of estrogen signaling pathway and the pleuripotential biologic activities of most organic chemicals--irrespective of their origin.

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Estrogen signaling in mammalian cells is primarily mediated at the molecular level by two members of the nuclear receptor superfamily--estrogen receptors alpha (ER-[alpha]) and beta (ER-[beta]). …